Improved diagnostics by exome sequencing following raw data reevaluation by clinical geneticists involved in the medical care of the individuals tested

Abstract

Purpose: Reanalysis of exome sequencing data when results are negative may yield additional diagnoses. We sought to estimate the contribution of clinical geneticists to the interpretation of sequencing data of their patients.

Methods: The cohort included 84 probands attending a tertiary genetics institute (2015-2018) with a nondiagnostic result on clinical exome sequencing performed in one of five external laboratories. The raw data were uploaded to the Emedgene bioinformatics and interpretation platform for reanalysis by a team of two clinical geneticists, the geneticist directly involved in the patient's care, and a bioinformatician.

Results: In ten probands (11.9%), a new definitive diagnosis was reached based on genes that were known to be associated with the phenotype at the time the original report was issued. The main reasons for a negative exome result were incorrect interpretation of the clinical context and absence of OMIM entry. Pathogenic variants in genes with previously unknown gene-disease associations were discovered to be causative in three probands. In total, new diagnoses were established in 13/84 individuals (15.5%).

Conclusion: Direct access to complete clinical data and shortening of time to including gene-phenotype associations in databases can assist the analytics team and reduce the need for additional unnecessary tests.

Keywords: bioinformatics; clinical exome; diagnostic yield; phenotype; reevaluation.